Cordarone

SIDE EFFECTS

Adverse reactions have been very common in virtually all
series of patients treated with Cordarone for ventricular arrhythmias with
relatively large doses of drug (400 mg/day and above), occurring in about
three-fourths of all patients and causing discontinuation in 7 to 18%. The most
serious reactions are pulmonary toxicity, exacerbation of arrhythmia, and rare
serious liver injury (see “WARNINGS”), but other adverse effects
constitute important problems. They are often reversible with dose reduction or
cessation of Cordarone treatment. Most of the adverse effects appear to become
more frequent with continued treatment beyond six months, although rates appear
to remain relatively constant beyond one year. The time and dose relationships
of adverse effects are under continued study.

Neurologic problems are extremely common, occurring in 20
to 40% of patients and including malaise and fatigue, tremor and involuntary
movements, poor coordination and gait, and peripheral neuropathy; they are
rarely a reason to stop therapy and may respond to dose reductions or
discontinuation (see “PRECAUTIONS”). There have been spontaneous reports
of demyelinating polyneuropathy.

Gastrointestinal complaints, most commonly nausea,
vomiting, constipation, and anorexia, occur in about 25% of patients but rarely
require discontinuation of drug. These commonly occur during high-dose
administration (i.e., loading dose) and usually respond to dose reduction or
divided doses.

Asymptomatic corneal microdeposits are present in
virtually all adult patients who have been on drug for more than 6 months. Some
patients develop eye symptoms of halos, photophobia, and dry eyes. Vision is
rarely affected and drug discontinuation is rarely needed.

Dermatological adverse reactions occur in about 15% of
patients, with photosensitivity being most common (about 10%). Sunscreen and
protection from sun exposure may be helpful, and drug discontinuation is not
usually necessary. Prolonged exposure to Cordarone occasionally results in a
blue-gray pigmentation. This is slowly and occasionally incompletely reversible
on discontinuation of drug but is of cosmetic importance only.

Cardiovascular adverse reactions, other than exacerbation
of the arrhythmias, include the uncommon occurrence of congestive heart failure
(3%) and bradycardia. Bradycardia usually responds to dosage reduction but may
require a pacemaker for control. CHF rarely requires drug discontinuation.
Cardiac conduction abnormalities occur infrequently and are reversible on
discontinuation of drug.

The following side-effect rates are based on a
retrospective study of 241 patients treated for 2 to 1,515 days (mean 441.3
days).

The following side effects were each reported in 10 to
33% of patients:

In surveys of almost 5,000 patients treated in open U.S.
studies and in published reports of treatment with Cordarone, the adverse
reactions most frequently requiring discontinuation of Cordarone included
pulmonary infiltrates or fibrosis, paroxysmal ventricular tachycardia, congestive
heart failure, and elevation of liver enzymes. Other symptoms causing
discontinuations less often included visual disturbances, solar dermatitis,
blue skin discoloration, hyperthyroidism, and hypothyroidism.

DRUG INTERACTIONS

Amiodarone is metabolized to desethylamiodarone by the
cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4
(CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and
intestines (see “CLINICAL PHARMACOLOGY, Pharmacokinetics”).
Amiodarone is an inhibitor of CYP3A4 and p-glycoprotein. Therefore, amiodarone
has the potential for interactions with drugs or substances that may be
substrates, inhibitors or inducers of CYP3A4 and substrates of p-glycoprotein.
While only a limited number of in vivo drug-drug interactions with amiodarone
have been reported, the potential for other interactions should be anticipated.
This is especially important for drugs associated with serious toxicity, such
as other antiarrhythmics. If such drugs are needed, their dose should be reassessed
and, where appropriate, plasma concentration measured. In view of the long and
variable half-life of amiodarone, potential for drug interactions exists, not
only with concomitant medication, but also with drugs administered after
discontinuation of amiodarone.

Since amiodarone is a substrate for CYP3A4 and CYP2C8,
drugs/substances that inhibit CYP3A4 may decrease the metabolism and increase
serum concentrations of amiodarone. Reported examples include the following:

Protease inhibitors

Protease inhibitors are known to inhibit CYP3A4 to
varying degrees. A case report of one patient taking amiodarone 200 mg and
indinavir 800 mg three times a day resulted in increases in amiodarone
concentrations from 0.9 mg/L to 1.3 mg/L. DEA concentrations were not affected.
There was no evidence of toxicity. Monitoring for amiodarone toxicity and
serial measurement of amiodarone serum concentration during concomitant
protease inhibitor therapy should be considered.

Histamine H1 antagonists

Loratadine, a non-sedating antihistaminic, is
metabolized primarily by CYP3A4. QT interval prolongation and Torsade de
Pointes have been reported with the co-administration of loratadine and
amiodarone.

Histamine H2 antagonists

Cimetidine inhibits CYP3A4 and can increase serum
amiodarone levels.

Antidepressants

Trazodone, an antidepressant, is metabolized
primarily by CYP3A4. QT interval prolongation and Torsade de Pointes have been
reported with the co-administration of trazodone and amiodarone.

Other substances

Grapefruit juice given to healthy volunteers
increased amiodarone AUC by 50% and Cmax by 84%, and decreased DEA to
unquantifiable concentrations. Grapefruit juice inhibits CYP3A4­mediated
metabolism of oral amiodarone in the intestinal mucosa, resulting in increased
plasma levels of amiodarone; therefore, grapefruit juice should not be taken
during treatment with oral amiodarone. This information should be considered
when changing from intravenous amiodarone to oral amiodarone (see “DOSAGE
AND ADMINISTRATION”).

Amiodarone inhibits p-glycoprotein and certain CYP450
enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A4. This inhibition can
result in unexpectedly high plasma levels of other drugs which are metabolized
by those CYP450 enzymes or are substrates of p-glycoprotein. Reported examples
of this interaction include the following:

Immunosuppressives

Cyclosporine (CYP3A4 substrate) administered in
combination with oral amiodarone has been reported to produce persistently
elevated plasma concentrations of cyclosporine resulting in elevated
creatinine, despite reduction in dose of cyclosporine.

HMG-CoA reductase inhibitors: The use of HMG-CoA
reductase inhibitors that are CYP3A4 substrates in combination with amiodarone
has been associated with reports of myopathy/rhabdomyolysis.

Limit the dose of simvastatin in patients on amiodarone
to 20 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and
maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be
required as amiodarone may increase the plasma concentration of these drugs.

Cardiovasculars

Cardiac glycosides: In patients receiving digoxin
therapy, administration of oral amiodarone regularly results in an increase in
the serum digoxin concentration that may reach toxic levels with resultant
clinical toxicity. Amiodarone taken concomitantly with digoxin increases the
serum digoxin concentration by 70% after one day. On initiation of oral
amiodarone, the need for digitalis therapy should be reviewed and the dose
reduced by approximately 50% or discontinued. If digitalis treatment is
continued, serum levels should be closely monitored and patients observed for
clinical evidence of toxicity. These precautions probably should apply to
digitoxin administration as well.

Antiarrhythmics

Other antiarrhythmic drugs, such as quinidine,
procainamide, disopyramide, and phenytoin, have been used
concurrently with oral amiodarone.

There have been case reports of increased steady-state
levels of quinidine, procainamide, and phenytoin during concomitant therapy
with amiodarone. Phenytoin decreases serum amiodarone levels. Amiodarone taken
concomitantly with quinidine increases quinidine serum concentration by 33%
after two days. Amiodarone taken concomitantly with procainamide for less than
seven days increases plasma concentrations of procainamide and n-acetyl procainamide
by 55% and 33%, respectively. Quinidine and procainamide doses should be
reduced by one-third when either is administered with amiodarone. Plasma levels
of flecainide have been reported to increase in the presence of oral
amiodarone; because of this, the dosage of flecainide should be adjusted when
these drugs are administered concomitantly. In general, any added
antiarrhythmic drug should be initiated at a lower than usual dose with careful
monitoring.

Combination of amiodarone with other antiarrhythmic
therapy should be reserved for patients with life-threatening ventricular
arrhythmias who are incompletely responsive to a single agent or incompletely
responsive to amiodarone. During transfer to amiodarone the dose levels of
previously administered agents should be reduced by 30 to 50% several days
after the addition of amiodarone, when arrhythmia suppression should be
beginning. The continued need for the other antiarrhythmic agent should be
reviewed after the effects of amiodarone have been established, and
discontinuation ordinarily should be attempted. If the treatment is continued,
these patients should be particularly carefully monitored for adverse effects,
especially conduction disturbances and exacerbation of tachyarrhythmias, as
amiodarone is continued. In amiodarone-treated patients who require additional
antiarrhythmic therapy, the initial dose of such agents should be approximately
half of the usual recommended dose.

Antihypertensives

Amiodarone should be used with caution in patients receiving
β-receptor blocking agents (e.g., propranolol, a CYP3A4 inhibitor)
or calcium channel antagonists (e.g., verapamil, a CYP3A4 substrate, and
diltiazem, a CYP3A4 inhibitor) because of the possible potentiation of
bradycardia, sinus arrest, and AV block; if necessary, amiodarone can continue
to be used after insertion of a pacemaker in patients with severe bradycardia
or sinus arrest.

Anticoagulants

Potentiation of warfarin-type (CYP2C9 and CYP3A4
substrate) anticoagulant response is almost always seen in patients receiving
amiodarone and can result in serious or fatal bleeding. Since the concomitant
administration of warfarin with amiodarone increases the prothrombin time by
100% after 3 to 4 days, the dose of the anticoagulant should be reduced by
one-third to one-half, and prothrombin times should be monitored closely.

Clopidogrel, an inactive thienopyridine prodrug,
is metabolized in the liver by CYP3A4 to an active metabolite. A potential
interaction between clopidogrel and Cordarone resulting in ineffective
inhibition of platelet aggregation has been reported.

Some drugs/substances are known to accelerate the
metabolism of amiodarone by stimulating the synthesis of CYP3A4 (enzyme
induction). This may lead to low amiodarone serum levels and potential decrease
in efficacy. Reported examples of this interaction include the following:

Antibiotics

Rifampin is a potent inducer of CYP3A4.
Administration of rifampin concomitantly with oral amiodarone has been shown to
result in decreases in serum concentrations of amiodarone and
desethylamiodarone.

Other substances, including herbal preparations

St. John's Wort (Hypericum perforatum) induces
CYP3A4. Since amiodarone is a substrate for CYP3A4, there is the potential that
the use of St. John's Wort in patients receiving amiodarone could result in
reduced amiodarone levels.

Other reported interactions with amiodarone

Sinus bradycardia has been reported with oral amiodarone
in combination with lidocaine (CYP3A4 substrate) given for local anesthesia.
Seizure, associated with increased lidocaine concentrations, has been reported
with concomitant administration of intravenous amiodarone.

Dextromethorphan is a substrate for both CYP2D6
and CYP3A4. Amiodarone inhibits CYP2D6.

Cholestyramine increases enterohepatic elimination
of amiodarone and may reduce its serum levels and t½.

Disopyramide increases QT prolongation which could
cause arrhythmia.

Fluoroquinolones, macrolide antibiotics, and azoles are
known to cause QTc prolongation. There have been reports of QTc prolongation,
with or without TdP, in patients taking amiodarone when fluoroquinolones,
macrolide antibiotics, or azoles were administered concomitantly. (See “WARNINGS,
Worsened Arrhythmia”.)

Hemodynamic and electrophysiologic interactions have also
been observed after concomitant administration with propranolol, diltiazem, and
verapamil.

Electrolyte Disturbances

Since antiarrhythmic drugs may be ineffective or may be
arrhythmogenic in patients with hypokalemia, any potassium or magnesium
deficiency should be corrected before instituting and during Cordarone therapy.
Use caution when coadministering Cordarone with drugs which may induce
hypokalemia and/or hypomagnesemia.